Abstract
Cholera toxin (CT) is a potent mucosal adjuvant and oral administration of ovalbumin (OVA) antigens plus CT induces OVA-specific CD8+ cytotoxic T lymphocytes (CTLs) and IgA production in intestinal mucosa. However, the mechanisms of induction of these immune responses remain unknown. Intestinal OVA-specific CD8+ CTLs were not induced by oral administration of the CT active (CTA) or CT binding (CTB) subunit as an adjuvant and CD11c+ DCs were involved in cross-priming of intestinal CTLs. CD8+CD103+CD11c+CD11b−DCs and DCIR2+CD103+CD11c+CD11b+ DCs were distributed in the intestinal lamina propria and mesenteric lymph nodes, both DC subsets expressed DEC-205, and the expression of co-stimulatory molecules such as CD80 and CD86 was enhanced in both DC subsets after oral administration of intact CT but not the CTA or CTB subunit. Intestinal DCs activated by the oral administration of OVA plus CT cross-presented OVA antigens and DCs that captured OVA antigen through DEC-205, but not DCIR2, could cross-present antigen. We found that oral administration of intact CT, but not the CTA or CTB subunit, enhanced cell death, cytoplasmic expression of high-mobility group box 1 protein (HMGB1) in epithelial cell adhesion molecule (EpCAM)+CD45− intestinal epithelial cells (IECs), and HMGB1 levels in fecal extracts. HMGB1 dose-dependently enhanced the expression of CD80 and CD86 on DCs in vitro, and intravenous or oral administration of glycyrrhizin, an HMGB1 inhibitor, significantly suppressed activation of mucosal DCs and induction of intestinal OVA-specific CTLs and IgA by oral CT administration. These results showed that oral administration of intact CT triggers epithelial cell death in the gut and the release of HMGB1 from damaged IECs, and that the released HMGB1 may mediate activation of mucosal DCs and induction of CTLs and IgA in the intestine.
Highlights
Cholera toxin (CT) is a potent mucosal adjuvant and oral administration of an antigen plus CT induces antigen-specific mucosal IgA and plasma IgG production[1]
We found that oral administration of intact CT, but not the CT active (CTA) or CT binding (CTB) subunit, enhanced cell death, cytoplasmic expression of high-mobility group box 1 protein (HMGB1) in epithelial cell adhesion molecule (EpCAM)+CD45− intestinal epithelial cells (IECs), and HMGB1 levels in fecal extracts
We assessed the distribution of CD8+CD103+CD11b− dendritic cells (DCs) and CD103+CD11b+ DCs20 in the intestinal lamina propria (LP), mesenteric lymph nodes (MLNs), and the spleen from mice, and analyzed the expression of DEC-205 or DCIR2 on DCs
Summary
Cholera toxin (CT) is a potent mucosal adjuvant and oral administration of an antigen plus CT induces antigen-specific mucosal IgA and plasma IgG production[1]. Official journal of the Cell Death Differentiation Association. Effective induction of exogenous antigen crosspresentation by DCs and subsequent priming of CTLs is important in vaccine development for tumors and pathogens. CD103+CD8α+ DCs that are CD11chiCD11blo subsets in the intestinal lamina propria (LP) have been shown to induce CTL activity in vivo[8]. DEC205+ DC subset and DCIR2+ DC subset have been shown to be associated with cross-presentation via MHC class I and presentation by MHC class II, respectively[9]. Both DEC-205 and DCIR2 belong to the C-type lectin family, which is involved in the capture, endocytosis, and processing of glycoprotein antigen[10]
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